Head and Neck Pathol (2014) 8:392–399
DOI 10.1007/s12105-014-0582-0
UPDATE IN GNATHIC PATHOLOGY. GUEST EDITORS: ANGELA CHI, DMD AND JOHN WRIGHT, DDS
The Diagnostic Usefulness of Immunohistochemistry
for Odontogenic Lesions
Keith D. Hunter • Paul M. Speight
Received: 30 September 2014 / Accepted: 30 October 2014 / Published online: 20 November 2014
 Springer Science+Business Media New York 2014
Abstract The diagnosis of odontogenic tumors can be
challenging, largely due to their rarity and consequent
difficulties in gaining experience in their assessment. In
most cases, careful attention to morphology, in conjunction
with clinical and radiological features will allow a diag-
nosis to be made. However, in some cases, immunohisto-
chemical analysis of the tumor may be useful. In this
review we will outline the immunohistochemical expres-
sion profile of normal developing odontogenic tissues and a
range of odontogenic tumors. In many cases the immuno-
histochemical markers are neither specific nor sensitive
enough to be of help in diagnosis, but in some cases such
analysis may prove very useful. Thus we have outlined a
limited number of circumstances where immunohisto-
chemistry may be of use to the practicing diagnostic
pathologist.
Keywords Odontogenic tumors

Immunohistochemistry
Ameloblastoma
Diagnosis
Introduction
Given their accepted rarity, investigation of the immuno-
histochemical profile of odontogenic tumors has lagged
behind those of other tumor types. However, in recent
years the number of publications reporting immunostaining
in a range of lesions of odontogenic origin has increased.
Some of these follow the increase in our understanding of
K. D. Hunter (&)
P. M. Speight
Unit of Oral and Maxillofacial Pathology, School of Clinical
Dentistry, University of Sheffield, Claremont Crescent,
Sheffield S10 2TA, UK
e-mail: k.hunter@sheffield.ac.uk
123
the immunophenotype of the developing tooth germ, while
others are wider applications of markers, which are well
understood in a number of other epithelial or mesenchymal
tumors. However, most of these publications have
addressed issues of pathogenesis and very few markers
have been found to be useful for the diagnostic pathologist.
Interestingly, in the current (2005) WHO classification,
there is no mention of a useful immunophenotype for
almost all of the odontogenic tumors [1].
In this review, we will outline circumstances where
immunohistochemistry (IHC) may be useful in the day-to-
day practice of the diagnostic pathologist. This by no
means minimises the interest in, or potential usefulness of
the large numbers of molecular markers whose expression
has been investigated, for which clinical utility has not
been established. It is undoubtedly true that for almost all
odontogenic tumors there are characteristic histological
features, and the diagnosis can be made with careful
attention to morphology, in conjunction with radiology and
other clinical features. Nevertheless, there are some prob-
lematic areas: cystic lesions, small biopsies, and the iden-
tification of malignant change for which IHC may offer
some help.
In order to contextualise the use of IHC in these tumors,
we will start by briefly revising the pattern of protein
expression in the developing tooth germ and in the dental
lamina rests from which many of these tumors arise, before
dealing with each of the main tumor types in turn.
Immunohistochemical Profile of Normal Odontogenic
Tissues
Tooth development is a complicated, highly coordinated
process with a number of sequential morphological stages.
Head and Neck Pathol (2014) 8:392–399
These stages demonstrate variable molecular profiles that
may overlap. The temporal changes in the profile of
cytokeratins have been investigated throughout odonto-
genesis. The odontogenic epithelium expresses keratins 7,
13, 14, and 19. In particular, CK14 stains odontogenic
epithelium in all stages of tooth development, including the
dental lamina and stellate reticulum, while CK19 is more
prominent in later stages [2, 3]. Many other molecular
markers have been demonstrated during odontogenesis,
particularly in relation enamel proteins and to transcription
factors, which control the order and morphology of teeth
[4, 5]. However, no suggestion of a clinical use in diagnosis
has been explored.
The remnants of odontogenic epithelium (rest cells of
Malassez and cell rests of Serres) show similar immun-
ophenotypes [6, 7]. In dogs, calretinin has been shown to
be expressed solely in odontogenic epithelium, and thus
may be a useful marker to distinguish odontogenic from
non-odontogenic epithelium [8]. Such investigations have
not been reported in human tissues.
Hamartomas/Odontoma
There is rarely any difficulty in diagnosing either complex
or compound odontoma. The small number of studies in the
literature suggest that the pattern of expression of a number
of molecular markers is very similar to that seen in normal
tooth development [2, 9].
One area of diagnostic difficulty is the so-called odon-
togenic gingival epithelial hamartoma (OGEH), which has
a differential diagnosis of peripheral ameloblastoma. The
case series addressing these lesions are small, and it is not
yet clear if these lesions are truly hamartomas or if they
are, as some suggest, an earlier form of odontogenic tumor
[10]. Molecular markers that may allow these distinctions
to be made would be most welcome, but as yet, none have
been suggested.
Neoplastic Odontogenic Epithelium
Ameloblastoma (and Tumors with Ameloblastoma-
Like Tissue)
A number of investigators have reported patterns of cyto-
keratin expression in ameloblastoma similar to normal
odontogenic tissues. In general, ameloblastomas express
cytokeratins 5/6, 13, 14 and 19, although expression may
vary in some subtypes (Fig. 1a–c) [2, 11, 12]. In solid/
multicystic ameloblastomas and unicystic ameloblastomas,
CK13 is preferentially expressed in the stellate reticulum-
like cells, CK14 in peripheral cells and CK19 in all cells,
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including areas of acanthomatous or granular cell differ-
entiation [12, 13]. This pattern does not hold for some
peripheral ameloblastomas or desmoplastic ameloblasto-
mas [12]. The expression of CK13 in stellate reticulum-like
cells is interesting as CK13 is not expressed in the stellate
reticulum of the developing tooth germ [2].
Variations in proliferation rate in the various amelo-
blastoma subtypes have been reported, with both peripheral
and desmoplastic ameloblastoma showing lower Ki-67
labelling indices [13–16]. Overall, however, all amelobl-
astomas have been shown to have a very low proliferative
index (Fig. 1f, reviewed in Gomes et al. [17]), and it is
possible that proliferation markers may be useful to help
diagnose malignant ameloblastomas, especially in small
biopsies [18]. However, this issue requires further explo-
ration to determine its clinical usefulness.
In conjunction with CK13, CK14, and CK19, CD56
(expressed in peripheral cells) and calretinin (expressed in
stellate reticulum-like cells), may be of use in small
biopsies or biopsies of cystic lesions. CD56 (or NCAM) is
expressed in the peripheral cells of the tumor islands in all
types of ameloblastoma (Fig. 1e) [19, 20], while calretinin
is reciprocally expressed in the stellate reticulum-like cells
[21, 22], including in most unicystic ameloblastoma
(although less frequent than in solid ameloblastoma [21,
23]). However, both markers are expressed, to a much
lesser extent, in odontogenic keratocyst/KCOT, thus using
markers in isolation to distinguish a cystic ameloblastoma
from odontogenic keratocyst (OKC)/keratocystic odonto-
genic tumor (KCOT) may still result in diagnostic uncer-
tainty [20, 24].
Odontogenic Keratocyst (OKC)/Keratocystic
Odontogenic Tumor (KCOT)
There is little evidence that IHC is helpful in the diagnosis
of OKC. The lesion has very typical and almost patho-
gnomonic features, which make diagnosis based on histo-
logical examination quite straightforward. Although there
have been many publications reporting the immunophe-
notype of OKC, these have all been directed at elucidating
the pathogenesis or in an attempt to determine the putative
neoplastic nature of the lesion. The profile of cytokeratin
expression in OKC is similar to that found in other odon-
togenic cysts (high molecular weight CKs and CK19 are
common) [25], although in addition, OKC will express
CK1 and CK10, which are markers of cornification.
However, these are not needed for diagnostic purposes
since this is evident on H&E staining. An area of diag-
nostic difficulty is in distinguishing inflamed OKC from
other cyst types, especially in small biopsies, but in these
cases the keratinisation pattern is lost and the keratin pro-
file is of no value.
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Fig. 1 Photomicrographs of immunohistochemical staining of a
solid/multicystic ameloblastoma, showing expression of CK5/6 (a),
CK14 (b), CK19 (c), CD56 (d), calretinin (e), and Ki-67 (f), showing
Proliferation markers, most often Ki-67, have often been
used to demonstrate a higher proliferation rate in OKC
compared to other cyst types. OKC show increased mitoses
and Ki-67 expression compared to other cyst types with
expression above the basal layers being characteristic. This
finding and evidence of PTCH gene expression has been
widely used as evidence of a neoplastic origin for this
lesion [26]. Discussion of this issue is not a subject of this
review, but suggestions that reduced PTCH protein
expression may be a marker for OKC, may provide evi-
dence of neoplastic origin, or may distinguish syndromic
from non-syndromic cysts have not been borne out.
Immunohistochemical studies have shown that PTCH
protein expression is similar in OKC, cystic ameloblasto-
mas and other types of odontogenic cysts [27]. There is
some evidence emerging that anti-apoptotic markers,
including bcl-2 and BAX, may be specifically increased in
OKC, but this needs confirmation and its diagnostic value
has not been considered [27, 28].
Calcifying Epithelial Odontogenic Tumor (CEOT)
Detailed immunohistochemical studies of CEOT are not
plentiful in the literature. The small number of studies
show expression of CK14 and CK19 (variable) by the
epithelial cells [2, 29]. Other investigations have demon-
strated a CEOT gene expression signature, the usefulness
of which has not been tested in a large cohort [30]. One
potentially diagnostically useful feature is the presence of
amyloid-like material in many tumors, which may become
calcified. Morphology and histochemical stains (Congo red
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Head and Neck Pathol (2014) 8:392–399
the variability of staining seen even within a small area in one tumor.
Total magnification 9200
or Thioflavin-T) are currently more likely to be of help than
IHC in its assessment. However, recent investigation of a
number of odontogenic epithelia associated proteins, such
as odontogenic ameloblast-associated protein (ODAM),
may yet yield useful biomarkers [31].
Recently a small series of CEOT was compared with a
number of cases of dental follicle, which contained CEOT-
like proliferations [29]. Classic CEOT showed a higher Ki-
67 index and expression of mini chromosome maintenance
(MCM) proteins, but this will require further investigation
before its usefulness is established.
Adenomatoid Odontogenic Tumor (AOT)
The immunophenotype of AOT is not clear with contra-
dictory results. In small case series, Angiero et al. showed
expression of CK5/6, CK17, and CK19 while others only
showed CK14 expression [2, 32]. The one large case series,
which presented a cohort with extensive overlap with
CEOT (36 of 39 showed CEOT-like areas), demonstrated
expression of CK5, CK14, and CK19 [33]. Interestingly, a
number also expressed CK7, although this was not in the
duct-like areas. No expression of calretinin has been shown
and a number of studies have pointed out that expression of
Ki-67 is very low or absent [32, 34, 35]. However, there are
few diagnostic difficulties presented by AOT and on the
whole, IHC does not seem to be helpful. The overlap
between AOT and CEOT seen in a minority of cases can
raise problems, but no immunohistochemical marker has
been reported which reliably distinguishes those that may
be hamartomas from neoplasms. Similar diagnostic
Head and Neck Pathol (2014) 8:392–399
difficulties present in differentiating AOT from adenoid
ameloblastoma with dentinoid in small biopsies [36] and
immunohistochemical markers to distinguish these entities
would be welcome.
Squamous Odontogenic Tumor (SOT)
The literature related to the SOT is largely that of indi-
vidual case reports, and although these were collated in a
comprehensive review, the immunophenotype is not well
established [37].
Lesions Containing Ghost Cells
The main lesions that contain ghost cells include the cal-
cifying cystic odontogenic tumor (CCOT) and solid vari-
ants (dentinogenic ghost cell tumor, DGCT), however,
ghost cells can be present focally in a wide range of other
odontogenic tumors. In CCOT, cytokeratins 14 and 19 have
been identified in the epithelial component, with CK6
expression in both the epithelium and ghost cells [38]. The
proliferation fraction, as assessed by Ki-67, is very similar
to ameloblastoma, particularly in those lesions where the
lining is obviously ameloblastoma-like [39, 40]. The solid
lesions show a similar immunophenotype [41].
Neoplastic Odontogenic Mesenchyme (With or Without
Epithelium)
Ameloblastic Fibroma (AF)
The mesenchymal component of the ameloblastic fibroma
resembles primitive dental pulp, and rarely will require
immunohistochemical analysis. Occasional mesenchymal
cells express S100, with juxta-epithelial GFAP expression
in ameloblastic fibrodentinoma associated with induction
of hard tissue formation [42]. Other studies have examined
various odontogenic tumors including AF; however,
because of the small number of cases examined, it is not
clear how representative these results are for AF as a
whole.
Odontogenic Fibroma (OF)
One study of reasonable size is present in the literature,
presenting the immunophenotype of 14 OFs, almost all of
which were epithelium-rich (formerly WHO-type). These
authors confirmed that the epithelial component had a very
similar pattern of cytokeratin expression as seen in other
odontogenic epithelia, namely expressing AE1/AE3, CK5,
CK14, CK19, and 34bE12 and negative for CK1 and
CK18. There were two cases weakly positive for CK7 and
395
CK8 [43]. The mesenchyme expressed vimentin and
occasional cells expressed SMA. The main diagnostic issue
in OF is that of the epithelium-poor type, where IHC may
be used to find or confirm the presence of epithelium, to
differentiate the lesion from desmoplastic fibroma or
fibromyxoma. However, careful attention to the morpho-
logical features with appropriate radiology is far more
useful.
Odontogenic Myxoma
The odontogenic myxoma may present diagnostic diffi-
culties due to morphological overlap with a number of non-
odontogenic lesions, from which it should be distinguished.
The mesenchymal component contains spindle-shaped
cells most of which express vimentin (Fig. 2a, b), with a
sub population in some tumors expressing actins [44]. An
epithelial component is unusual, but when present
expressed CK14, and showed a very low proliferation
fraction. There is disagreement in the literature over
expression of CK19 [44, 45]. The main issue in the dif-
ferential diagnosis of odontogenic myxoma is distinction
from myxoid variants of other tumors, including myxoid
neural (e.g. schwannoma, neurofibroma), myofibroblastic
(myxoid nodular fasciitis), muscle (myxoid rhabdomyo-
sarcoma) and lipomatous tumors (myxolipoma), amongst
others [46]. Occasionally there is need for distinction from
myxoid change in an enlarged dental follicle. In this regard,
an odontogenic myxoma should ideally not express S100 or
CD34 (except in vasculature) or any of the muscle markers,
or CD68. However, S100 expression has been reported, a
finding which may compound difficulties in distinction
from myxoid peripheral nerve sheath tumors [45]. Fur-
thermore, it has been suggested that the identification of
S100 expressing small nerve fibres may indicate an
enlarged dental follicle rather than an odontogenic myx-
oma [45]. In many cases, a clear origin within the alveolus
is very helpful, but IHC may be warranted in more difficult
sites such as the posterior maxilla, where it is more difficult
to be certain of an origin within the tooth-bearing portion
of the jaws.
Malignant Odontogenic Tumors
An area of particular difficulty in the diagnosis of odon-
togenic tumors is that of malignancy, particularly when it
arises in a pre-existing benign lesion. A number of inves-
tigators have shown that the cytokeratin profile character-
istic of ameloblastoma (e.g. CK14 and CK19 expression) is
largely similar in ameloblastic carcinoma and has no
diagnostic utility (Fig. 3a–e) [16]. Many other reports
centre on the proliferation fraction as a means of
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Fig. 2 H&E stained section of odontogenic myxoma (a) with immunohistochemical staining for vimentin expression in the same tumour (b).
Total magnification 9200
Fig. 3 An H&E stained section (a) and immunohistochemical
staining of a case of ameloblastic carcinoma, showing expression of
CK14 (b), CK19 (c), CD56 (d), calretinin (e), and Ki-67 (f), showing
the variability of staining seen even within a small area in one tumor.
distinguishing these two entities. However, while all show
a higher Ki-67 proliferation fraction in ameloblastic car-
cinoma than in ameloblastoma, the reported rates vary
from 2.9–14.9 % in ameloblastoma and 8–48.7 % in
ameloblastic carcinoma (compare Figs. 1f, 3f) [14–16].
This means that while a focal area of increased Ki-67
expression in a given tumor may suggest progression to
malignancy, it is not possible to give even an estimate of a
cut-off percentage to help make a diagnosis of ameloblastic
carcinoma, except if the fraction is uniformly very high
(e.g. over 20 %). Thus, morphological features including
the cytological features of malignancy and a prominent
infiltrative and destructive growth pattern are likely to be
more useful [16]. However, a number of newer immuno-
histochemical markers have been suggested, such as
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Head and Neck Pathol (2014) 8:392–399
CK19 and CD56 expression have been lost with calretinin only
staining a few cells in the centre of the tumor nests. Total
magnification 9200
nuclear SOX2 expression [47], and these may prove useful
markers to identify malignant ameloblastic tumours.
The presence of clear cells can also create diagnostic
uncertainty, given the extensive differential diagnosis such
a finding can raise. However, in many cases careful
attention to morphology will remove most uncertainty.
There are occasions when distinction between clear cell
odontogenic carcinoma (CCOC) and other carcinomas
containing clear cells may require histochemical or
immunohistochemical stains. CCOC will demonstrate PAS
positive, but mucin negative, material in cells, and often
(but not always) express CK19 (Fig. 4a, b) and calretinin
[48, 49]. Other IHC which may be useful include markers
for clear cell variant of melanoma (S100, Melan A),
myoepithelial markers if salivary gland neoplasia is
Head and Neck Pathol (2014) 8:392–399
Fig. 4 Photomicrographs of immunohistochemical staining of an
illustrative case of clear cell odontogenic carcinoma showing
progression to higher grade tumor with loss of CK19 expression
suspected (calponin, SMA, p63), and immuno-histochem-
ical markers for metastases which may contain clear cells,
such as renal (RCC, CD10) and prostate (PSA) carcinomas.
In some cases, distinction from clear cell salivary tumors
arising from minor glands associated with the jaws may not
be possible [50]. More recently it has been shown that clear
cell odontogenic carcinoma shows EWSR1 gene rear-
rangements, which are common to many other clear cell
carcinomas including salivary [51]. Although this is a
molecular finding, IHC for a fusion protein may become
available and may allow differentiation of CCOC from
clear cell variants of other odontogenic tumors.
Another area where molecular markers have proved
useful is in the diagnosis of mucoepidermoid carcinomas
(MEC), which have been shown to contain specific
MAML2 rearrangements. Intraosseous MECs are probably
of odontogenic origin and must be differentiated from
glandular odontogenic cysts (GOC). GOC lack the
MAML2 rearrangement and FISH can be used to confirm
the diagnosis [52]. Antibodies to MAML2 fusion proteins
are available and IHC may be useful for the differential
diagnosis of MEC from GOC, but this has not yet been
reported.
Summary: The Use of IHC in Diagnosis of Odontogenic
Lesions (a Practical Guide)
From the above review of the literature it can be seen that the
number of diagnostically useful IHC markers that have been
demonstrated in odontogenic tumors is very small, and in
most cases clinical history, radiology, and careful attention
to morphology is sufficient to establish a diagnosis. It is also
worth bearing in mind that most of the immunophenotypes
described here are lost in areas of intense inflammation, and
this has to be considered when assessing any pattern of
immunohistochemical staining in these lesions. However,
397
(a) and increase in Ki-67 expression (b). Total magnification 9200.
Photomicrographs courtesy of Dr. Bill Barrett, UK
careful application of what is known about the immuno-
phenotype in the key areas of diagnostic uncertainty may be
useful in the following circumstances:
• Differential diagnosis of myxoma and clear cell lesions
to exclude variants and metastases from elsewhere.
• IHC for fusion proteins may be useful in clear cell
lesions and to confirm or exclude an intraosseous MEC.
• A high proliferation rate (perhaps over 20 %) may be a
helpful indicator of malignancy in ameloblastomas.
• Pan-cytokeratin markers may be helpful to confirm the
presence of odontogenic epithelium in epithelial-poor
odontogenic fibromas.
• In cystic lesions, the combination of widespread CD56
expression in peripheral cells and calretinin expression
in the superficial cells supports a diagnosis of amelo-
blastoma over OKC/KCOT.
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